Ethnobotany/ethnopharmacology and mass bioprospecting: issues on intellectual property and benefit-sharing.

Ethnobotany/ethnopharmacology has contributed to the discovery of many important plant-derived drugs. Field explorations to seek and document indigenous/traditional medical knowledge (IMK/TMK), and/or the biodiversity with which the IMK/TMK is attached, and its conversion into a commercialized product is known as bioprospecting or biodiversity prospecting. When performed in a large-scale operation, the effort is referred to as mass bioprospecting. Experiences from the mass bioprospecting efforts undertaken by the United States National Cancer Institute, the National Cooperative Drug Discovery Groups (NCDDG) and the International Cooperative Biodiversity Groups (ICBG) programs demonstrate that mass bioprospecting is a complex process, involving expertise from diverse areas of human endeavors, but central to it is the Memorandum of Agreement (MOA) that recognizes issues on genetic access, prior informed consent, intellectual property and the sharing of benefits that may arise as a result of the effort. Future mass bioprospecting endeavors must take heed of the lessons learned from past and present experiences in the planning for a successful mass bioprospecting venture.

Preclinical antitumor and toxicologic profile of carboplatin.

Carboplatin, an analog of the antitumor drug Platinol, was selected for clinical evaluation on the basis of its experimental antitumor and toxicologic profile in animal models. Described in this review is a detailed summary of selected preclinical data accumulated on carboplatin as well as data obtained concomitantly using Platinol. The predominant result gleaned from the experimental antitumor data is that of comparability between the two compounds, a finding which we feel best reflects the emerging clinical data. With respect to the preclinical toxicology, carboplatin was found to be less nephrotoxic and less emetic than Platinol. This pattern of toxicity for carboplatin appears to be substantiated in the clinical setting.

Antitumor activity and toxicity in animals of RR-150 (7-cysteaminomitosane), a new mitomycin derivative.

The experimental antitumor activity of a new mitomycin derivative, 7-cysteaminomitosane (RR-150), was evaluated in mice. When administered i.p. to mice bearing i.p.-implanted tumors, RR-150 was superior to mitomycin C (MMC) in increasing the life span of animals bearing P388 leukemia, B16 melanoma, and a line of L1210 leukemia partially resistant to MMC. RR-150 appeared comparable to MMC in increasing life span of mice bearing Madison 109 lung carcinoma, Colon 26 carcinoma, or parental (nonresistant) L1210 leukemia. Mice immunosuppressed with 550 rads whole-body irradiation prior to i.p. implantation of B16 still benefited (e.g., 40% cure rate) following optimal RR-150 therapy when compared to nonirradiated, B16-implanted mice given RR-150 (e.g., 70% cure rate). RR-150 had inconsistent activity in the treatment of s.c.-implanted tumors. In toxicity evaluations, RR-150 was comparable to MMC in suppression of total while blood cell counts but appeared to be less neutropenic. RR-150 also caused less cumulative leukopenia than did MMC in a weekly chronic dose experiment. Based on serum chemistries, RR-150 did not have significant nephrotoxicity, but there was evidence of possible liver toxicity at doses near the 50% lethal dose. Because of the balance of favorable antitumor and toxicity properties of RR-150, work is under way to prepare a more bioavailable form for advanced evaluation.

cis-4-[[[(2-Chloroethyl)nitrosoamino]carbonyl]methylamino] cyclohexanecarboxylic acid, a nitrosourea with latent activity against an experimental solid tumor.

cis-4-[[[(2-Chloroethyl)nitrosoamino]carbonyl]methylamino] cyclohexanecarboxylic acid (N-Me-cis-CCCNU) was synthesized in five steps from cis-4-aminocyclohexanecarboxylic acid via an N-tosylated intermediate. N-Me-cis-CCCNU, which is incapable of the facile decomposition that characterizes the clinically useful nitrosoureas, effected a significant cure rate of both early and established murine Lewis lung carcinoma, even though its in vitro half-life was approximately 5.5 times that of the unmethylated parent compound. This is the first observation of latent activity of a nitrosourea against an experimental solid tumor.

Evaluation of Madison 109 lung carcinoma as a model for screening antitumor drugs.

The Madison 109 lung carcinoma (M109) was evaluated as a model for the screening of antitumor agents. Thirty-five drugs with established antitumor activity were assayed in mice implanted ip or sc with M109. Depending on the mode of tumor implantation, drugs representing those affecting nucleic acids (through binding, interacalating, or inducing single-strand breaks), various alkylating agents, mitotic inhibitors, antimetabolites, and immunomodulators were able either to inhibit the growth of sc M109 or to extend the lifespan of mice given M109 ip. The ip implanted tumor was, for example, markedly affected (median survival time of treated/control mice, x 100: greater than or equal to 200% with occasional cures) by doxorubicin, mitomycin C, 10-hydroxy camptothecin, and dihydroxyanthraquinone. The sc implanted tumor, however, was markedly affected (treated - control of greater than or equal to 12 days with regard to median time to grow 1-g tumors) by bleomycin and an analog, talisomycin, and by 6-thioguanine. The M109 was responsive to many different classes of clinically active agents and can serve as a useful tool in the screening of drugs with such potential. It may be particularly useful in screening analogs of camptothecins, nitrosoureas, bleomycins, and mitomycins as well as for evaluating anthraquinones, anthracyclines, mitotic inhibitors, antimetabolites, and immunomodulators.

Antileukemia (L1210) activity and toxicity of cis-dichlorodiammineplatinum(II) analogs.

cis-Dichlorodiammineplatinum(II) (cis-platinum) and 40 of its analogs were evaluated for antitumor activity in BDF1 mice implanted ip with 10(6) L1210 leukemia cells. Several of these analogs were also evaluated for their ability to cause elevation in BUN and to produce leukopenia in normal BDF1 mice. In 11 experiments, cis-platinum given on Day 1 or Days 1--9 after implant produced T/C (treated/control) values between 164% and 214% and 157% and 285% respectively. On the basis of single experiments, 13 analogs were judged to be comparable to cis-platinum in that they produced T/C values greater than or equal to 167% after a single dose or greater than or equal to 200% after daily doses for 9 days. These active compounds included various substituted amine derivatives of dichloroplatinum(II), malonatoplatinum(II), aquasulfatoplatinum(II), and chloroacetatoplatinum(II) and derivatives of dihydroxydichloroplatinum(IV). Twelve of these active analogs and cis-platinum were evaluated for toxicity at doses ranging from near the optimal therapeutic dose to greater than or equal to the LD50. Only five of the 12 analogs and cis-platinum caused an increase in BUN to greater than 30 mg/100 ml, while eight of the analogs produced leukopenia comparable in incidence and severity to that produced by cis-platinum.